2011 Annual Report
1a.Objectives (from AD-416)
The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharamceuticals or agrichemicals and to identify, characterize and develop medicinal plants for production of pharmaceuticals as potential alternative crops.
1b.Approach (from AD-416)
The approach includes a program of: (1) Discovery of secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays [NP301, C4, PS 4B]; (2) Characterizing mechanisms of action, selectivity, toxicity and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models [NP301, C4, PS 4B]; and (3)Selection, agronomics and analysis of medicinally important plants and their derived products [NP301, C4, PS 4B].
Researchers at the National Center for Natural Products Research (NCNPR) at the University of MS, Oxford, MS, maintained basic discovery operations, with emphasis on the discovery of antifungals, anticancer, anti-inflammatory agents and immunomodulating agents. Continued to source plant materials for screening from our own plant collections and from numerous collaborators. Added 3,000 plant samples to our inventory this year. Screened over 8,000 natural product crude extracts, semi-purified fractions and purified compounds for biological activities against specific molecular targets and whole cell systems. As part of our continuing effort in the search for anti-infective, anti-cancer, and immunomodulator/anti-inflammatory leads from natural sources, more than 200 compounds (including 50 new natural products) were identified from plants, marine sponges, and fungi. Many showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 600 of our isolated actives or extracts have been characterized in more detailed follow-up assays to determine their mode of action, pharmaceutical properties, toxicity, and selectivity across a range of assays. In addition to these basic operations we have selected a number of these compounds for more advanced study, whether for characterizing mechanisms of action, determining suitability for further pharmaceutical development, evaluation in disease models in preclinical studies, or in field applications. Advanced 7 new leads this year to animal testing. Tested the efficacy of several urushiol derivatives [the toxic principle of poison ivy] for desensitization to poison ivy dermatitis in animal models. These have been developed under a Small Business Initiative Research grant from the National Institutes of Health, in collaboration with ElSohly Laboratories, Inc. A patent application has been filed for these compounds. The Medicinal Plant Garden at the University of Mississippi has undergone relocation this year with the construction of new facilities begun in September, 2009 and expected to be completed in August, 2011. The new facilities include a laboratory building, horticulture building, greenhouse, shade house, equipment building, and several acres of outdoor growing sites, including a pond for aquatic species. These facilities will enhance the capabilities of NCNPR to cultivate and process medicinal plants to be used in the discovery program. NCNPR began a major construction project this year to complete its major research building with a 90,000 sq. ft. research wing. Construction documents are presently under review by the funding agencies (Health Resources and Services Administration; National Institutes of Health), and groundbreaking will occur in 2011. The new research wing will expand and enhance the research capabilities of NCNPR with a second plant specimen repository, herbarium, and laboratories for plant tissue cultures, cellular cultures, scale-up isolation and synthetic chemistry.
Discovery of new drugs to prevent or treat diseases caused by protozoans. New drugs for malaria and leishmaniasis will reduce risk of treatment failure, reduce risk of developing resistance, and reduce side-effects. The National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, continued screening for antimalarial and antileishmanial activities of natural products and synthetic analogs. We have also added new assays for the intracellular stages of leishmania and for anti-trypanosomal activity. Several additional publications and isolations of novel anti-protozoal natural products have resulted from these. These accomplishments contribute to efforts to fight these widespread diseases.
Develop agents for prevention/treatment of poison ivy dermatitis. Poison ivy is a widespread plant that causes an itching rash in most people who touch it. Research for developing new leads that are effective in animals in the prevention of poison ivy dermatitis has continued under a project funded by the National Institutes of Health. Two lead compounds have been licensed by Hapten Technology. These accomplishments may lead to new products for a common, but serious condition.
Develop treatments for cancer. A cancer research program requires a drug discovery program in order to explore all avenues of treatment. This year NCNPR established the Drug Discovery Core of the University of Mississippi Medical Center (UMMC) Cancer Institute. The National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, core group has developed new screening assays that target signal-transduction pathways known to be involved in the expression of cancers, and has begun screening plant extracts for anti-cancer activity. The most promising anti-cancer compounds will be produced in quantities required for further development and evaluation by the UMMC Cancer Institute.
Develop antifungal natural products. Because many organisms contain inherent protective mechanisms the natural environment is a rich source for compounds to treat fungal diseases. The antifungal drug discovery program at the National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, aims to discover novel antifungal compounds for treating life-threatening opportunistic fungal infections. It covers various aspects of drug discovery including screening and isolation of natural product antifungal compounds, determining their mechanism of action, and understanding potential resistance mechanisms. In this past year, over 4,000 natural product samples were screened for antifungal activity against 5 different fungal pathogens, and over 100 “hits” were identified. A variety of molecular and genetic mechanistic studies were conducted on 8 different antifungal compounds, and 3 potentially novel antifungal pathways were identified. Several important achievements have resulted in the past year including: (a) the isolation and identification of new antifungal compounds, and (b) the identification of a new molecular pathway (calcium signaling) targeted by a marine-derived antifungal compound – this pathway is new in that it is not targeted by current clinically used antifungal drugs. These accomplishments may lead to new treatments for numerous diseases of plants, animals, and humans.
Xu, T., Feng, Q., Jacob, M.R., Avula, B., Mask, M.M., Baerson, S.R., Tripathi, S.K., Mohammed, R., Hamann, M.T., Khan, I.A., Walker, L.A., Clark, A.M., Agarwal, A.K. 2011. The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis. Antimicrobial Agents and Chemotherapy. 55(4):1611-1621.
Li, J., Jadhav, A.N., Khan, I.A. 2009. Triterpenoids from Brazilian Ginseng, Pfaffia paniculata. Planta Medica. 75:1-5.
Avula, B., Wang, Y., Duzgoren-Aydin, N.S., Khan, I.A. 2010. Inorganic elemental compositions of commercial multivitamin/mineral dietary supplements: application of collision/reaction cell inductively coupled-mass spectroscopy. Food Chemistry. 127:54-62.
Mikell, J.R., Herath, W., Khan, I.A. 2011. Microbial metabolism Part 12 isolation characterization and bioactivity evaluation of eighteen microbial metabolites of 4'-hydroxyflavanone. Chemical and Pharmaceutical Bulletin. 59(6):692-697.
Kumarihamy, M., Fronczek, F.R., Ferreira, D., Jacob, M., Khan, S.I., Nanayakkara, D. 2010. Bioactive 1, 4-Dihydroxy-5-phenyl-2-pyridinone alkaloids from Septoria pistaciarum. Journal of Natural Products. 73:1250-1253.
Li, X., Babu, K., Jacob, M.R., Khan, S.I., Agarwal, A.K., Clark, A.M. 2011. Natural product-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium scaffold as a new antifungal template. ACS Medicinal Chemistry Letters. 2:391-395.
Xu, M., Zhang, Y., Li, X., Jacob, M.R., Yang, C. 2010. Steroidal saponins from fresh stems of Dracaena angustifolia. Journal of Natural Products. 73:1524-1528.
Liu, H., Walker, L.A., Nanayakkara, N., Doerksen, R.J. 2011. Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase. Journal of the American Chemical Society. 133:1172-1175.
Khan, S.I., Zhao, J., Khan, I.A., Walker, L.A., Dasmahapatra, A.K. 2011. Potential utility of natural products as regulators of breast cancer-assoicated aromatase promoters. Reproductive Biology and Endocrinology. 9:91-101.
Moraes, R.M., Lata, H., Sumyanto, J., Pereira, A.M., Bertoni, B.W., Joshi, V.C., Pugh, N.D., Khan, I.A., Pasco, D.S. 2011. Characterization and pharmacological properties of in vitro propagated clones of Echinacea tennesseensis (Beadle) small. Plant Cell Tissue And Organ Culture. 106:309-315.
Rahman, A., Samoylenko, V., Jacob, M.R., Sahu, R., Jain, S.K., Khan, S.I., Tekwani, B.L., Muhammad, I. 2011. Antiparasitic and antimicrobial indolizidines from the leaves of Prosopis glandulosa var glandulosa from Nevada and Texas USA. Planta Medica. doi.org/10.1055/s-0030-127096.
Li, X., Ferreria, D., Ding, Y. 2010. Determination of absolute configuration of natural products: theoretical calculation of electronic circular dichroism as a tool. Current Organic Chemistry. 14:1678-1697.